ABSTRACT TGF1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multi-functional cytokine has limited development of global TGF1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibited TGF1-induced epithelial-mesenchymal transition without immediate TGF1 receptor (TR) kinase inhibition. We identified trihydroxyphenolic compounds as potent (IC50 ~ 50 nM) blockers of TGF1 responses, Snail1 expression, and pathological collagen deposition in vivo. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2) thereby limiting effects to fibroblast or fibroblast-like cells. Mechanistic studies revealed the trihydroxyphenolics to induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a novel metabolite directly inhibiting TRI kinase. The central hypothesis of this proposal is that a unique LOXL2-dependent metabolite of trihydroxyphenolic compounds selectively and effectively blocks TGF1-dependent signaling in fibroblasts and thereby can abrogate the pro-fibrotic lung environment of mouse and humans burdened by progressive fibrosis without the toxicities associaed with global TGF1 inhibition. The proposal aims to define the exact metabolite of LOXL-2 processing of trihydroxyphenolics, further test the fibroblast specificity of one of these, epigallocatechin gallate (EGCG), in TGF1 signaling among all cell types isolated from IPF lungs, and execute a proof-of-principle pilot study in ILD patients with lung fibrosis, testing the hypothesis that oral EGCG will both block LOXL2 activity in fibrotic lungs in vivo and suppress lung collagen 1, Snail1, and pSmad3 accumulation. The goal of these studies is to generate sufficient data to compel the acquisition of funding to test a non- patentable, inexpensive agent such as EGCG as a therapeutic in a phase 2 clinical trial of IPF patients.